The objectives of the current proposal are to deepen our understanding at the fundamental level of the hormonal control of calcium and skeletal metabolism and to apply this knowledge to assessment of the pathophysiology of hormonal disturbances in disorders of calcium metabolism and thereby improve efforts at diagnosis and treatment of these diseases. A variety of chemical, immunochemical, metabolic and biochemical analyses will be applied to studies of parathyroid hormone, calcitonin and vitamin D in humans and animals. Studies of the isolation, sequence analysis and synthesis of the peptide hormones will be coupled with analysis of the biosynthesis, secretion and metabolism of parathyroid hormone and calcitonin. Particular interest centers on pro-parathyroid hormone and a larger precursor, pre-proparathyroid hormone. The production, metabolic transformation and blood transport of vitamin D will be assessed in relation to calcium homeostasis. The significance of the newly recognized complex metabolism and interrelated actions of the peptide hormones and of vitamin D will be systematically assessed in normal human subjects, other mammalian species and in patients with hypercalcemia, hypocalcemia and skeletal disorders. The mode of hormone action will be studied at the cellular and biochemical level, with particular emphasis on interaction of the hormones with their bioreceptors in target cells in kidney and bone. Specific clinical applications through improved assays for parathyroid hormone, calcitonin and vitamin D will be made to the diagnosis and treatment of hyperparathyroidism, medullary carcinoma of the thyroid, calcium and vitamin D deficiency states, osteomalacia, Paget's disease of bone and hypocalcemic disorders. BIBLIOGRAPHIC REFERENCES: Goltzman, D., Peytremann, A., Callahan, E., Segre, G.V. and Potts, J.T., Jr.: Metabolism and biological activity of parathyroid hormone in renal cortical membranes. J. Clin. Invest. 57: 8-19, 1976. Habener, J.F., Mayer, G.P., Dee, P.C. and Potts, J.T., Jr.: Metabolism of amino- and carboxyl-sequence immunoreactive parathyroid hormone in the bovine: evidence for peripheral cleavage of hormone. Metabolism 25: 385-395, 1976.